Browsing by Author "Voss, R."

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    Age-dependent phenotypic and molecular evolution of pediatric MDS arising from GATA2 deficiency
    (2025) Kotmayer, L.; Kozyra, E.J.; Kang, G.; Strahm, B.; Yoshimi, A.; Sahoo, S.S.; Pastor, V.B.; Attardi, E.; Voss, R.; Vinci, L.; Kaiser, M.; Dworzak, M.N.; De Moerloose, B.; Sukova, M.; Stary, J.; Hasle, H.; Jahnukainen, K.; Polychronopoulou, S.; Kallay, K.; Catalan Martinez, Paula Valentina
    GATA2 deficiency is an autosomal dominant transcriptopathy disorder with high risk for myelodysplastic syndrome (MDS). To elucidate genotype-phenotype associations and identify new genetic risk factors for MDS, we analyzed 218 individuals with germline heterozygous GATA2 variants. We observed striking age-dependent incidence patterns in GATA2-related MDS (GATA2-MDS), with MDS being absent in infants, rare before age 6 years, and steeply increasing in older children. Among 108 distinct GATA2 variants (67 novel), null mutations conferred a 1.7-fold increased risk for MDS, had earlier MDS onset compared to other variants (12.2 vs. 14.6 years, p = 0.009) and were associated with lymphedema and deafness. In contrast, intron 4 variants exhibited reduced penetrance and lower risk for MDS development. Analysis of the somatic landscape revealed unique patterns of clonal hematopoiesis. SETBP1 mutations occurred exclusively in patients with monosomy 7 and their frequency decreased with age. Conversely, the frequency of STAG2 mutations and trisomy 8 increased with age and appeared protective against early development of advanced MDS. Overall, the majority (73.9%) of mutation-positive cases harbored monosomy 7, suggesting it serves as a major driver in malignant progression. Our findings provide evidence for age-appropriate surveillance, and a foundation for genotype-driven risk stratification in GATA2 deficiency.